Nanoparticle Cell Penetration - Aerosols: Measurement, Dosimetry, and Health Effects - page 220

can have marked effects on the type of response seen. In the 2008 study by Mercer et al. (2008),
they tested the hypothesis of whether exposure to more dispersed single-walled carbon nanotube
(SWCNT) structures would alter pulmonary distribution and response. Using pharyngeal aspiration
as a route of lung exposure, they noted that a highly dispersed solution of SWCNTs led to a low
observation of macrophage phagocytosis (potentially indicating low macrophage uptake) and no
formation of granulomatous lesions that are common after lung administration of CNTs (Lam et al.,
2004; Warheit et al., 2004; Ma-Hock et al., 2009). The authors concluded that dispersed SWCNTs
are rapidly incorporated into the alveolar interstitium and that they produce an increase in collagen
deposition.
It is obvious to see that the aggregation/agglomeration state of a particle will have effects on the
zone of deposition within the lung based on alteration of the aerodynamic diameter of aggregate/
agglomerate in relation to the primary particle and this in turn will affect the clearance rate and
structures with which the particle can interact in the lung. In addition, the size of the agglomerate
and propensity for disagglomeration/aggregation may also affect the potential for trans- or paracel-
lular translocation and associated pathology (e.g., localized airway granuloma formation versus
interstitial ibrosis or perhaps). Inhaled particles such as air pollution (Mitchev et al., 2002) and
high aspect ratio particles (e.g., asbestos ibers) (Boutin et al., 1996) are known to translocate from
the lung into the pleural cavity and even the peritoneal cavity. Here, material such as long ibers
may be retained at points of egress from the pleural cavity where they can be associated with the
formation of pleural pathologies. This translocation and retention of high aspect ratio materials
has raised questions about high aspect ratio nanoparticles such as CNTs (Donaldson et al., 2010).
Indeed such concern has been further exacerbated by the observation of subpleural deposition of
CNT in the lungs (Ryman-Rasmussen et al., 2009) and even pleural transfer of CNT from the lung
into the pleural space (Mercer et al., 2010). This has now suggested a shift in the question away from
simply “can high aspect ratio nanoparticle translocate into the pleural space,” to “what do they do
when they reach there?”. Indeed studies with asbestos and mineral ibers have shown that longer
iber length is associated with greater inlammogenicity (Davis et al., 1986; Moalli et al., 1987;
Donaldson et al., 1989; Ye et al., 1999) and evidence is emerging that certain multiwalled CNTs
exhibit length-dependent inlammogenic/pathogenic effects (Poland et al., 2008). Recent studies
have tried to address the issue of pleural retention and resultant effects of high aspect ratio nanopar-
ticles, which has suggested that long ibrous particles are retained in the pleural space with resultant
stimulation of inlammation and ibrosis. In contrast, short ibers or particulates are able to escape
the pleural space and localize in the mediastinal lymph nodes (Murphy et al., 2011).
9.4 TRANSLOCATION TO THE CIRCULATORY SYSTEM
Although there is a lack of any substantial epidemiology on the effects of exposure to engineered
nanoparticles, the best guide as to likely effects on the cardiovascular system comes from studies
such as the American Cancer Society studies (Pope et al., 2003) and the implication of combustion-
derived nanoparticles (CDNP) in such adverse cardiovascular effects of PM 10 /PM 2.5 . As regards
mechanisms, the evidence is accumulating for an impact on the endothelium and on atherothrombo-
sis (Brook et al., 2003; Mills et al., 2007b). As a result, there is considerable interest in investigating
how or if engineered nanoparticles might similarly impact cardiovascular disease.
Very little is known of the role of structure on translocation to the blood insofar as only low-
toxicity, low-solubility nanoparticles have been studied. However, analogously to the situation with
interstitialization, the increased permeability caused by inlammation could aid penetration to the
blood. Changing the size and surface reactivity, factors that would inluence inlammogenicity, may
be considered likely modiiers of the potential of any nanoparticle to translocate to the blood and
subsequent cardiovascular effects.
From the few studies of the toxicokinetics of a range of different nanoparticles in rats following
inhalation (Kreyling et al., 2002, 2004, 2007; Oberdörster et al., 2002), there is some evidence that